Sphingosine-1-phosphate [(2S,3R,4E)-2-amino-3-hydroxyoctadeca-4-enyl-1-phosphate; hereinafter sometimes abbreviated as S1P] is a lipid which is synthesized by metabolic turnover of sphingolipids or extracellular action of secretory sphingosine kinases. It is proposed that this lipid acts as an intercellular transmitter and an intracellular secondary transmitter.
With regard to S1P2 (EDG-5/AGR16/H218) receptors among S1P receptors, it has been published that the strong expression of mRNA thereof is confirmed in tissues of heart, lung, stomach and small intestine and that the expression amount of mRNA thereof in intimal cells in model mice of carotid balloon injury which are the model for coronary arteriosclerosis is significantly decreased compared to normal intimal cells (see Patent Document 1).
It is also reported that S1P receptors (particularly S1P2 receptors) are involved in portal hypertension, asthma and the like (see Non Patent Document 1). It is also known that the receptors are involved in expression of connective tissue growth factors (CTGFs) associated with onset of fibrosis, cancer and the like (see Non Patent Document 2).
The following compounds are known as the related art of the present invention.
As the compounds having S1P2 antagonistic activity, pyrazopyridine compounds or pharmaceutically acceptable salts thereof represented by the formula (a):
wherein R1a, R2a and R3a represent a C1-8 alkyl group and the like; R4a represents a hydrogen atom and the like; R5a and R6a are the same or different and represent a hydrogen atom, a C1-8 alkyl group, a C1-6 alkoxy group, a halogen atom and the like; Xa represents —NH—, —O—, —CH2— and the like; Ya represents —NH— and the like; Za represents —CO— and the like; Wa represents —NH— and the like; and the ring Aa represents an aryl group, a heteroaryl group and the like (the definitions of respective groups are abstracted), have been disclosed which specifically act on S1P2 receptors and are useful as therapeutics for fibrosis (see Patent Document 2).
The known compounds having S1P2 antagonistic activity also include compounds having a piperidine skeleton represented by the formula (b):
[C 3]Ab-Xb—Yb—Zb—Bb   (b)wherein Ab represents a cyclic group which may contain a substituent; Xb represents a single bond or a spacer having 1 to 3 atoms in the main chain; Yb represents a single bond or a spacer having 1 to 3 atoms in the main chain; Zb is a single bond or a spacer having 1 to 3 atoms in the main chain; and Bb represents a cyclic group which may contain a substituent (see Patent Document 3) and compounds having an azetidine skeleton (see Patent Document 4).
Meanwhile, as the compounds having a benzene skeleton substituted with two cyclic groups, the compounds represented by the formula (c):
wherein P1c and P2c independently represent a bond or a C1-3 alkyl; Ac represents CH or N; Bc represents CH or N; R1c represents a hydrogen, an amino, —NR4c—CO—ZcR9cR13c and the like; R3c represents —C(NR17c)NH2 or when Ac is CH, R3c also represents an amino C1-7 alkyl; R10c, R14c and R15c independently represent a hydrogen, a halogen, a C1-7 alkyl and the like; Qc represents a hydrogen or a halogen; R4c represents a hydrogen or a C1-7 alkyl; Zc is a 5- to 12-membered saturated, partially saturated or aromatic ring which may be monocyclic or bicyclic; R9c and R13c independently represent a hydrogen, a halogen, a C1-7 alkyl and the like; R2c represents a C1-7 alkyl, a phenyl which may be substituted and the like; and R17c represents a hydrogen, —OH, a C1-7 alkoxy and the like (the definitions of respective groups are abstracted), are known as matriptase inhibitors (see Patent Document 5).
No prior art documents discloses or suggests that the compound of the invention which contains two cyclic groups, particularly phenoxy groups at specific substitution positions have significantly improved human S1P2 antagonistic activity.
Patent Document 1: Japanese Patent Application Laid-open No. H6-234797
Patent Document 2: WO 01/98301
Patent Document 3: WO 2004/002531
Patent Document 4: WO 2005/063704
Patent Document 5: WO 2010/133748
Non Patent Document 1: Biochemical and Biophysical Research Communications, vol. 320, No. 3, p. 754-759, 2004
Non Patent Document 2: Molecular Cancer Research, vol. 6, No. 10, p. 1649-1656, 2008